Cytomegalovirus (CMV) and all members of Herpesvirales derived from a progenitor herpesvirus (HV) ~200M years ago. As obligate intracellular pathogens, the fact that HV's remain extant to infect their hosts suggests sophisticated viral mechanisms to counter host immune responses. The sophistication of viral immunomodulation is emphasized by the ability of HV's to maintain a lifelong persistence within immune competent hosts. Emerging evidence indicates that a common mechanistic link by which different CMV members attenuate the functionality of host immunity is by targeting the cellular interleukin-10 (cIL-10) signaling pathway. Only primate CMV's (HCMV and RhCMV) encode a viral version of cIL-10 (cmvIL-10 and rhcmvIL-10) that, despite extreme genetic drift from the originally transduced cIL-10 gene, has the identical immunosuppressive properties of cIL10. In parallel approaches conducted in rhesus macaques (RM), we have shown that rhcmvIL-10 is essential for (i) acute and long-term modulation of host immune responses and (ii) enabling long-term shedding of virus in bodily fluids following parenteral RhCMV challenge. Our results indicate that rhcmvIL-10 is a critical viral determinant that skews virus-host interactions towards those that favor the establishment of a persistence in an immune competent host. We hypothesize that immunization of na?ve monkeys against rhcmvIL-10 will significantly increase resistance to mucosally transmitted RhCMV challenge. Our study will demonstrate that vaccine-mediated neutralization of rhcmvIL- 10 can protect against repeated mucosal exposure to RhCMV through the following Aims. (1) Immunization of naive RM with non-functional forms of rhcmvIL-10, RhCMV gB, and rhcmvIL-10 + gB.; (2) Mucosal challenge of immunized RM by introducing them into a cohort of RhCMV- excreting RM under housing conditions that enable horizontal transmission of RhCMV; (3) Development and in vitro characterization of non-functional forms of HCMV cmvIL-10; (4) Vaccination of RM with non-functional HCMV cmvIL-10 and in vitro demonstration of (i) broadly cross-reactive neutralizing antibodies (N-Ab) against HCMV cmvIL-10 sequence variants, and (ii) an absence of antibodies that are cross-reactive with human cIL-10.